Methamphetamine (METH) is a psychomotor stimulant that is strongly associated with increases in sexual drive and behavior in both women and men. Even though men and women are equally as likely to be addicted to or use METH, studies of sexual behavior often focus on male users. The paucity in studies examining the effect of METH in women is of great concern, when one considers the high correlation with sexually transmitted diseases such as HIV/AIDS and unplanned pregnancies. In fact, why METH so profoundly increases sexual drive is unknown and, to our knowledge, relatively unexplored. In our recent work, we have employed a rodent model to examine the effects of METH on female sexual behavior and the underlying neural circuitry. We found that METH enhances sexual motivation in females, but this enhancement is dependent upon progesterone. Additionally, the combined administration of ovarian hormones (estradiol and progesterone) and METH enhances the neuronal activation in the medial amygdala and the ventromedial nucleus of the hypothalamus, two brain nuclei implicated in female sexual behaviors. Thus, the broad, long-term objective of the current application is to understand the cellular and molecular mechanisms mediating the drug-sex nexus in females. We will employ a novel approach that utilizes a lesion technique that selectively targets neurons involved in mediating the effects of METH, thus establishing their role in the drug-sex nexus. The specific aims of the current proposal are to (i) establish whether a specific subpopulation of medial amygdala neurons is responsible for METH enhanced female sexual motivation, (ii) determine if METH and ovarian hormones induce structural and neurochemical plasticity in medial amygdala and (iii) investigate the cellular and molecular mechanisms underlying the drug- sex nexus. The significance of advancing our understanding of the neurobiology that links female sexual motivation and METH use is the potential to uncover new foundations for the biological basis of addiction in women that involve the intersection of ovarian hormones, natural reward and drug-induced reward. PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) use among women is a burgeoning health concern as its abuse is significantly associated with high-risk sexual behaviors that have been correlated with increasing rates of sexually transmitted diseases such as HIV/AIDS and unplanned pregnancies among addicted women. Studies of sexual behavior often focus on male users, even though men and women are equally likely to be addicted to or use METH. Thus, the paucity in studies examining the link between METH and female sexual behavior has left a gap in our understanding of the neurobiology and neurocircuitry underlying the drug-sex nexus in females. Why METH so profoundly increases sexual drive is unknown and to our knowledge relatively unexplored. A better understanding of the neurobiology linking female sexual motivation and METH use may elucidate better therapeutic strategies to reduce high-risk sexual behaviors among women using METH.